Novel water-soluble nanocrystals comprising a low molecular weight coating reagent, and methods of preparing the same

Abstract

The invention relates to a water soluble nanocrystal with a nanocrystal core comprising at least one metal M 1 selected form an element of main group II, VIIA, subgroup VIIA, subgroup IB, subgroup IIB, main group III or main group IV of the periodic system of the elements (PSE), at least one element A selected from main group V or main group VI of the PSE, a capping reagent attached to the surface of the core of the nanocrystal, said capping reagent having at least two coupling groups, and a second layer comprising a low molecular weight coating reagent having at least two coupling moieties covalently coupled with the coating reagent, and at least one water soluble group for conferring water solubility to the second layer.

1 . A water soluble nanocrystal comprising:
 a nanocrystal core comprising at least one metal M 1  selected from an element of subgroup Ib, subgroup IIb, subgroup IVb, subgroup Vb, subgroup VIb, subgroup VIIb, subgroup VIIb, main group II, main group III or main group IV of the periodic system of the elements (PSE), and further comprising   a first layer comprising a capping reagent attached to the surface of the core of the nanocrystal, said capping reagent having at least two coupling groups,   and a second layer comprising a low molecular weight coating reagent having at least two coupling moieties covalently coupled with the coating reagent, and at least one water soluble group for conferring water solubility to the second layer.   
     
     
         2 . A water soluble nanocrystal comprising:
 a nanocrystal core comprising at least one metal M 1  selected from an element of main group II, subgroup VIIA, subgroup VIIIA, subgroup IB, subgroup IIB, main group III or main group IV of the periodic system of the elements (PSE), and at least one element A selected from main group V or main group VI of the PSE, and further comprising   a first layer comprising a capping reagent attached to the surface of the core of the nanocrystal, said capping reagent having at least two coupling groups,   and a second layer comprising a low molecular weight coating reagent having at least two coupling moieties covalently coupled with the coating reagent, and at least one water soluble group conferring water solubility to the second layer.   
     
     
         3 . The nanocrystal of  claim 2 , wherein the capping reagent comprises a terminal group having affinity for the surface of the core of the nanocrystal. 
     
     
         4 . The nanocrystal of  claim 3 , wherein the terminal group is selected from the group consisting of sulfhydryl, amino, amine-oxide and phosphino groups. 
     
     
         5 . The nanocrystal of  claim 2 , wherein the at least two coupling groups of the capping reagent are spaced apart from the terminal group by a hydrophobic region. 
     
     
         6 . The nanocrystal of  claim 4 , wherein each of the at least two coupling groups comprises a functional group independently selected from amino, hydroxyl, carbonyl, carboxyl, nitrile, nitro, isocyanate, epoxide, anhydride and halide groups. 
     
     
         7 . The nanocrystal of  claim 2 , wherein the capping reagent is a molecule having the formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 X is a terminal group selected from S, N, P, or O═P, 
 R a  is a moiety comprising at least 2 main chain carbon atoms, 
 Y is selected from N, C, —COO—, or —CH 2 O—, 
 Z is a moiety comprising a polar functional group, 
 k is 0 or 1, 
 m is an integer from 1 to 3, 
 n is an integer from 0 to 3, and 
 n′ is an integer from 0 to 2, wherein n′ is selected to satisfy the valence requirement of Y. 
 
     
     
         8 . The nanocrystal of  claim 7 , wherein the moiety F, comprises 2 to 50 main chain atoms. 
     
     
         9 . The nanocrystal of  claim 7 , wherein R a  is selected from the group consisting of alkyl, alkenyl, alkoxy and aryl moieties. 
     
     
         10 . The nanocrystal of  claim 9 , wherein each of R a  is a moiety independently selected from the group consisting of ethyl, propyl, butyl, pentyl, cyclopentyl, cyclohexyl, cyclo-octyl, ethoxy, and benzyl. 
     
     
         11 . The nanocrystal of  claim 7 , wherein Z is a functional group selected from the group consisting of amino, hydroxyl, carbonyl, carboxyl, nitrile, nitro, isocyanate and halide groups. 
     
     
         12 . The nanocrystal of  claim 11 , wherein Z comprises 2 to 50 main chain atoms. 
     
     
         13 . The nanocrystal of  claim 12 , wherein Z further comprises an amide or an ester linkage. 
     
     
         14 . The nanocrystal of  claim 2 , wherein the capping reagent comprises two identical coupling groups. 
     
     
         15 . The nanocrystal of  claim 14 , wherein the capping reagent is a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The nanocrystal of  claim 2 , wherein the capping reagent comprises two different coupling groups. 
     
     
         17 . The nanocrystal of  claim 16 , wherein the capping reagent is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The nanocrystal of  claim 2 , wherein the coupling group of the capping reagent comprises a polymerizable unsaturated carbon-carbon bond. 
     
     
         19 . The nanocrystal of  claim 18 , wherein the capping reagent is selected from the group consisting of w-thiol terminated methyl methacrylate, 2-butenethiol, (E)-2-Butene-1-thiol, S-(E)-2-butenyl thioacetate, S-3-methylbutenyl thioacetate, 2-quinolinemethanethiol, and S-2-quinolinemethyl thioacetate. 
     
     
         20 . The nanocrystal of  claim 2 , wherein the coating reagent comprised in the second layer comprises a water soluble molecule having the general formula (II): 
       
         
           
           
               
               
           
         
       
       wherein
 T is a hydrophilic moiety, 
 R c  is a moiety comprising at least 2 main chain carbon atoms, 
 G is selected from N, P or C, or Si 
 Z′ is a coupling moiety, 
 m′ is 2 or 3, 
 n is 1 or 2, and 
 n′ is 0 or 1, wherein n′ is selected to satisfy the valence requirement of G. 
 
     
     
         21 . The nanocrystal of  claim 20 , wherein T comprises a functional group selected from the group consisting of carboxyl, amino, nitro, hydroxyl, carbonyl groups and derivatives thereof. 
     
     
         22 . The nanocrystal of  claim 20 , wherein R c  comprises 3 to 6 main chain carbon atoms. 
     
     
         23 . The nanocrystal of  claim 20 , wherein Z′ comprises at least 6 main chain carbon atoms. 
     
     
         24 . The nanocrystal of  claim 23 , wherein Z′ further comprises at least one functional group selected from the group consisting of amino, hydroxyl, carbonyl, carboxyl, nitrile, nitro, isocyanate, epoxide, anhydride and halide groups. 
     
     
         25 . The nanocrystal of  claim 24 , wherein each of the coupling moieties Z′ are identical. 
     
     
         26 . The nanocrystal of  claim 25 , wherein the coating reagent is selected from the group consisting of a diamine, dicarboxylic acid, and a diol. 
     
     
         27 . The nanocrystal of  claim 26 , wherein the diamine is selected from 2,4-diaminobutyric acid or 2,3-diaminopropionic acid. 
     
     
         28 . The nanocrystal of any one of  claims 26 , wherein the coating reagent is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein CD is cyclodextrin, and 
       
         
           
           
               
               
           
         
       
     
     
         29 . The nanocrystal of  claim 24 , wherein each of the coupling moieties Z′ are different. 
     
     
         30 . The nanocrystal of  claim 29 , wherein the coating reagent is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         31 . The nanocrystal of  claim 18 , wherein the coating reagent comprises a diene. 
     
     
         32 . The nanocrystal of  claim 31 , wherein the diene is selected from the group consisting of 1,4-butadiene, 1,5-pentadiene and 1,6-hexadiene. 
     
     
         33 . The nanocrystal of  claim 2 , wherein the nanocrystal is a core-shell nanocrystal. 
     
     
         34 . The nanocrystal of  claim 33 , wherein the metal is selected from the group consisting of Zn, Cd, Hg, Mn, Fe, Co, Ni, Cu, Ag, and Au. 
     
     
         35 . The nanocrystal of  claim 33 , wherein the element A is selected from the group consisting of S, Se, and Te. 
     
     
         36 . The nanocrystal of  claim 35 , wherein the nanocrystal is a core shell nanocrystal selected from the group consisting of CdS, CdSe, MgTe, CdTe, ZnS, ZnSe, ZnTe, HgS, HgSe, and HgTe. 
     
     
         37 - 43 . (canceled) 
     
     
         44 . The nanocrystal of  claim 2 , further comprising a molecule having binding affinity for a given analyte being conjugated to the second layer of the polymer shell. 
     
     
         45 - 46 . (canceled) 
     
     
         47 . A method of detecting an analyte using a nanocrystal as defined in  claim 2 . 
     
     
         48 . A method of preparing a water soluble nanocrystal comprising:
 providing a nanocrystal core comprising at least one metal M 1  selected from an element of subgroup Ib, subgroup IIb, subgroup IVb, subgroup Vb, subgroup VIb, subgroup VIIb, subgroup VIIIb, main group II, main group III or main group IV of the periodic system of the elements (PSE),   reacting the nanocrystal core with a capping reagent, thereby attaching the capping reagent to the surface of the nanocrystal core and forming a first layer surrounding the nanocrystal core,   and   coupling the capping reagent with a low molecular weight coating reagent having at least at least two coupling moieties that are reactive towards the at least two coupling groups of the capping reagent, and at least one water soluble group for conferring water solubility to the second layer, thereby forming a second layer covalently coupled to the first layer and completing the formation of a water soluble shell surrounding the nanocrystal core.   
     
     
         49 . A method of preparing a water soluble nanocrystal comprising:
 providing a nanocrystal core comprising at least one metal M 1  selected from the group consisting of an element of subgroup IIB-VIB, IIIB-VB or IVB, main group II or main group III of the periodic system of the elements (PSE), and at least one element A selected from an element of the main group V or VI of the periodic system of the elements,   reacting the nanocrystal core with a capping reagent, thereby attaching the capping reagent to the surface of the nanocrystal core and forming a first layer surrounding the nanocrystal core,   and   coupling the capping reagent with a low molecular weight coating reagent having at least at least two coupling moieties that are reactive towards the at least two coupling groups of the capping reagent, and at least one water soluble group for conferring water solubility to the second layer, thereby forming a second layer covalently coupled to the first layer and completing the formation of a water soluble shell surrounding the nanocrystal core.   
     
     
         50 . The method of  claim 49 , wherein the capping reagent is hydrophilic. 
     
     
         51 . The method of  claim 49 , wherein the capping reagent is hydrophobic. 
     
     
         52 . The method of  claim 49 , wherein each coupling group present in the capping reagent comprises a functional group selected from amino, hydroxyl, carbonyl, carboxyl, nitrile, nitro, isocyanate, epoxide, anhydride and halide groups. 
     
     
         53 . The method of  claim 49 , wherein the capping reagent has the formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 X is a terminal group selected from S, N, P, or O═P, 
 R a  is a moiety comprising at least 2 main chain carbon atoms, 
 Y is selected from N, C, —COO—, or —CH 2 O—, 
 Z is a moiety comprising a polar functional group, 
 k is 0 or 1, 
 n is an integer from 0 to 3, 
 n′ is an integer from 0 to 2, wherein n′ is selected to satisfy the valence requirement of Y, and 
 m is an integer from 1 to 3. 
 
     
     
         54 . The method of  claim 53 , wherein the capping reagent is a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         55 . The method of  claim 49 , further comprising the step of activating the coupling groups of the capping reagent before coupling the coating reagent to the capping reagent. 
     
     
         56 . The method of  claim 55 , wherein the step of activating comprises reacting the nanocrystal comprising the first layer of capping reagent with a coupling agent. 
     
     
         57 . The method of  claim 56 , wherein the coupling agent is selected from the group consisting of 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide (EDC), sulfo-N-hydroxysuccinimide, N,N′-Dicyclohexylcarbodiimide (DCC), N,N′-dicyclohexyl carbodiimide, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, and N-hydroxysuccinimide. 
     
     
         58 . The method of  claim 49 , wherein coupling the capping reagent with a coating reagent comprises adding the coating reagent and the coupling agent together to a solution containing nanocrystal cores having the first layer. 
     
     
         59 . The method of  claim 49 , wherein the coupling is carried out in an aqueous buffer solution. 
     
     
         60 . The method of  claim 59 , wherein the aqueous buffer solution comprises a phosphate or ammonium buffer solution. 
     
     
         61 . The method of  claim 49 , wherein the coupling is carried out in a polar organic solvent. 
     
     
         62 . The method of  claim 61 , wherein the organic solvent is selected from the group consisting of pyridine, DMF, and chloroform. 
     
     
         63 . The method of  claim 49 , wherein the coating reagent comprised in the second layer comprises a water soluble molecule having the general formula (II): 
       
         
           
           
               
               
           
         
       
       wherein
 T is a hydrophilic moiety, 
 R e  is a moiety comprising at least 2 main chain carbon atoms, 
 G is selected from N, P or C, or Si 
 Z′ is a coupling moiety, 
 m′ is 2 or 3, 
 
       n is 1 or 2, and 
       n′ is 0 or 1, wherein n′ is selected to satisfy the valence requirement of G. 
     
     
         64 . The method of  claim 63 , wherein the coating reagent is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein CD is cyclodextrin, and 
       
         
           
           
               
               
           
         
       
     
     
         65 . The method of  claim 49 , further comprising reacting the polymer comprised in the second layer with a reagent suitable for exposing water soluble groups present in the second layer.